Appropriate regulation of osteoclast-mediated bone resorption is essential for maintenance of healthy bone. Understanding the molecular regulation of osteoclasts may lead to new therapeutic approaches to common serious bone diseases like osteoporosis. Osteoclasts resorb bone by generating an acidic compartment on the bone surface. A key component of the osteoclast acid transport mechanism is a chloride channel which is expressed in the osteoclast-ruffled border. The applicant's long-term goals have been to identify the molecular basis of the ruffled border chloride channel and to understand how this channel may regulate acid transport and bone resorption. The Specific Aims of the present proposal are to: (1) complete molecular cloning of the sequences encoding the ruffled membrane chloride channel; (2) biochemically characterize the channel complex; (3) explore the relationship between the chloride channel and the non-receptor tyrosine kinases, src, and; (4) define the mechanism by which the presence of bone regulates expression of the chloride channel.